Oxytocin was one of the first peptide hormones to be isolated and sequenced. It is a nonapeptide with two cysteine residues that form a disulfide bridge between positions 1 and 6 and corresponds to the formula

A similar nonapetide is mesotocin having the formula

For a long time the only effects attributed to oxytocin were its stimulating effects on milk ejection and uterine contractions, but in the past decades it has been shown that oxytocin exerts a wide spectrum of effects within the central nervous system, CNS. It has been suggested that oxytocin participates in the control of memory and learning processes and of various types of behaviour such as feeding, locomotion, as well as maternal and sexual behavior. Oxytocin is also suggested to participate in the control of cardiovascular functions, thermoregulation, and pain threshold and fluid balance. There is also evidence that oxytocin is involved in the control of various immunological processes. It has recently been demonstrated that oxytocin injections cause a lowering of blood pressure and increased weight gain—long lasting effects after repetitive administration. As a central stimulating substance oxytocin plays an important role in the interaction between mother and progeny in mammals. The products may also be used prophylactic in young human beings e.g. already in new born babies or young children to prevent the development of diseases later on in life which diseases are dependent on stress conditions during the fetal life. Such conditions may be heart/vessel diseases such as stroke, heart infarct, hypertension, and diabetes.
In the human body oxytocin is produced in the paraventricular nucleus, PVN, and the supraoptic nucleus, SON, of the hypothalamus. It differs by only two amino acids from vasopressin, which is also produced in these nuclei. The magnocellular oxytocinergic neurones of the SON and PVN send oxons to the posterior pituitary from which oxytocin is released into the circulation. Parvocellular neurones that originate in the PVN project into multiple areas within CNS. The oxytocin-producing cells are innervated by cholinergic, catecholaminergic as well as peptidergic neurones. The presence of oxytocin in different tissues outside the brain, such as the uterus, ovaries, testis, thymus, adrenal medulla and pancreas has been demonstrated and oxytocin is suggested to exert local effects in these organs.
A parallel secretion of oxytocin into the brain regions and into the circulation occurs in response to some stimuli such as suckling, but other stimuli can cause separate activation of oxytocinergic neurones, terminating in the brain or the pituitary.
Mesotocin, which has been isolated from frogs, has similar effects as oxytocin.
The oxytocin and mesotocin molecule may be digested into smaller fragments. Of special interest are fragments containing 2-4 peptides obtained by cleavage amino acids from the amino terminal and/or the carboxyl terminal. As used in the context of the present invention, the term “di-, tri- and tetrapeptide fragments of oxytocin or mesotocin” correspond to such fragments. Such fragments may either be amidated or not at the C-terminal. It has now been shown that di-, tri- and tetrapeptide fragments of oxytocin or mesotocin may be used in order to create eustasis.
By the expression “eustasis” we understand a psychophysiological state, i e a combination of a psychological and physiological state. The psychological state is characterised by calm and positive social interactions such as trust and breast-feeding. The physiological state is characterised by muscle relaxation, lowered cardiovascular activity and enhanced gastrointestinal activity. Besides, pulse rate and blood pressure are kept at a low, healthy and balanced level, and the vagally controlled gastrointestinal tract is activated, promoting digestion and storage of nutrients.
Eustasis should not be confused with euphoria, which is more an intense feeling of joy and reward. Furthermore, the creation of eustasis should not be confused with the treatment of depression or any other disease states. For example, the treatment of depression refers to a conversion from a disease state to a healthy state, whereas the creation of eustasis refers to a conversion from one healthy state to another healthy state.
In the Examples, some compounds according to the invention are administered to rats. A decrease in locomotor activity, blood pressure and hormone levels was noticed, suggested that the compounds have a eustasis creating effect.
U.S. Pat. No. 5,767,083 (D1) discloses the use of Pro-Leu-Gly-NH2 (SEQ ID NO: 8)and Pro-Ile-Gly-NH2 (SEQ ID NO: 9). The first-mentioned oligopeptide is called melanocyte stimulating inhibitory factor, abbreviated MIF, and is used against depression. Furthermore, D1 describes the combination of such oligopeptides known antidepressants such as amitriptyline, fluoxetine, and sertraline.
EP 146 113 (D2) discloses that Pro-Leu-Gly-NH2 (SEQ ID NO: 9) may be used against disease states caused by elevated melanotropine levels, such as high blood pressure. D2 also discloses the dipeptide Leu-Gly-NH2 (SEQ ID NO: 17).
Regulatory Peptides From Molecular Biology to Function, Advances in Biochemical Psychopharmacology, Vol. 33, Ed. E. Costa and M. Trabucchi, Raven Press, New York (1982) (D3) discloses the effect of Leu-Gly-NH2 (SEQ ID NO: 17), acetic acid salt in the treatment of neuropsychiatric illness.
No documents disclose tetrapeptide fragments of oxytocin and mesotocin. As mentioned above, some di- and tripeptide fragments of oxytocin and mesotocin are previously known in the art. However, it is not previously known to use di- and tripeptide fragments of oxytocin and mesotocin in order to create eustasis. Besides, no pharmaceutical compositions comprising the di- and tripeptides and oxytocin or mesotocin are known in the art.